The candidate, Soledad Cabeza de Vaca, holds a Ph.D. degree in Psychology from the City University of New York. She is currently a Research Assistant Professor of Psychiatry at New York University School of Medicine. The goals of the K01 Award are to gain additional skills in pharmacology, immunocytochemistry, autoradiography and enzyme assays to complement a strong background in behavioral science. These skills will enhance the candidate's ability to do independent research. The New York University School of Medicine and the laboratories of Drs. Eric Simon, Jacob Hiller, Kenneth Carr and Sarah Leibowitz (Rockefeller University) represent an outstanding environment for further training and career development. There is a close neurobiological relationship between ingestive behavior and drug addiction. A particularly robust finding is that food restriction augments the rewarding and cellular activating effects of abused drugs. Recently, several neuropeptides have been discovered that are responsive to food restriction and exert powerful appetite-stimulant (orexigenic) and -suppressant (anorexigenic) effects. The proposed research investigates whether these peptides modulate rewarding and addictive properties of drugs. First, orexigenic and anorexigenic peptide analogue that act via the melanocortin receptor subtype 4 (MC-4r), will be injected into the brain ventricular system and their modulatory effects on amphetamine reward and locomotion will be evaluated using intracranial self-stimulation and shuttle paradigms, respectively (specific aims #1 and #2). This will be followed by measurement of neuropeptide density and receptor binding in reward-related brain regions (specific aim #3 and #4). Regional neuroadaptations detected will guide microinjection experiments aimed at localization of brain regions that mediate peptide effects on amphetamine-induced behavior (specific aim #5). In light of evidence that the anorexigenic ligand of the MC-4r, (alpha-MSH, has anti-opiate effects, MC-4 receptor agonists and antagonists will also be evaluated for modulatory effects on the development of behavioral (specific aim #6) and biochemical (specific aim #7) indices of morphine tolerance and dependence. It is expected that the proposed studies will elucidate neuropeptidergic mechanisms that co-regulate energy balance and vulnerability to drug addiction.